Causal effects of gut microbiota on diabetic kidney disease: insights from 16S rRNA sequencing and bidirectional Mendelian randomization

Dysbiosis of the gut microbiome plays a critical role in diabetic kidney disease (DKD) development and progression. We stratified 46 type 2 DKD patients from Ruijin Hospital into early or advanced DKD groups in this cross-sectional study. Fecal samples underwent 16S rRNA sequencing. Statistical analyses (t-tests, Chi-square, GLMs) and MR were performed using SPSS and R. We found that advanced DKD patients exhibited distinct gut microbiota profiles, with LEfSe analysis showing higher <i>Butyricimonas</i>, <i>Fusicatenibacter</i>, and <i>Barnesiella</i> and lower <i>Allisonella</i> compared to early DKD, while DKD-susceptible individuals had elevated <i>Fusobacterium</i> and reduced <i>Allisonella</i> and <i>Eubacterium</i>. GLMs linked <i>Barnesiella</i>, <i>Streptococcus</i>, <i>Fusobacterium</i> to DKD susceptibility (<i>p</i> < 0.05), and <i>Slackia</i> and <i>Eubacterium</i> to early/resistant DKD. MR analysis demonstrated causality: <i>Barnesiella</i> (OR: 2.382), <i>Butyricimonas</i> (OR: 1.278), <i>Desulfovibrio</i> (OR: 2.518), and <i>Hemophilus</i> (OR: 1.622) worsened DKD, whereas <i>Slackia</i> and <i>Allisonella</i> protected against eGFR decline (<i>p</i> < 0.05). Reverse MR revealed the bidirectional effects-severe DKD increased <i>Ruminococcus</i>2 but suppressed <i>Allisonella</i> and <i>Akkermansia</i> (<i>p</i> < 0.05), underscoring microbiota-DKD interplay. Sensitivity analyses (MR-Egger, weighted median, leave-one-out) confirmed the robustness and directionality of these causal effects. In conclusion, 10 key bacterial genera were causally linked to DKD progression and susceptibility, including harmful (<i>Barnesiella</i>, <i>Butyricimonas</i>, <i>Desulfovibrio</i>, <i>Hemophilus</i>, <i>Bacteroides</i>, <i>Streptococcus</i>, <i>Ruminococcus</i>2) and protective taxa (<i>Slackia</i>, <i>Allisonella</i>, <i>Akkermansia</i>). These genera serve as novel biomarkers for early detection and risk stratification, and as potential therapeutic targets for microbiota-modulating interventions to mitigate DKD progression. The bidirectional microbiota-DKD interplay further underscores the promise of targeting gut dysbiosis in DKD precision management.